Epilepsy is a leading neurological disorder, second only to stroke. One to four million Americans and twenty to forty million people world-wide suffer from some form of epilepsy, making it second only to stroke as the leading neurological disorder. Although standard therapy permits control of seizures in 80% of these patients, one-half million people in the U.S. have uncontrolled epilepsy. The number of drugs useful for the treatment of epilepsy is remarkably small. Fewer than 20 drugs are currently marketed in the U.S., and of these, only five or six are widely used. Complex partial epilepsy (also known as temporal lobe, psychomotor or limbic epilepsy), the most devastating form among adults, and estimated to account for as many as two-thirds of all cases, is refractory to drug treatment Gummit, R. J., "The Epilepsy Handbook, The Practical Management of Seizures", Raven Press, New York, 1983!. It is becoming increasingly evident that significant progress toward complete control can be achieved only by an understanding of the mechanisms of the epilepsies themselves, which will provide the molecular basis for antiepileptic drug design and development, and new treatment strategies.
NMDA (N-methyl-D-aspartate) receptor overstimulation by high levels of the excitatory amino acid (EAA), L-glutamate, has been implicated in epileptogenesis and epilepsy Cavalheiro, et al., "Frontiers in Excitatory Amino Acid Research", A. R. Liss, New York, 1988!. Thus, development of agents that are EAA/NMDA antagonists may constitute novel and effective therapies for the epilepsies. Although a number of EAA inhibitors have been discovered, many lack NMDA receptor specificity and are too toxic for clinical studies Porter, Epilpsia, 30 S29-34, 1989!. Thus, the discovery of this invention of certain hydrazones, hydrazines, semicarbazones and thiosemicarbazones derived from pyridyl ketones, as a superior class of anticonvulsant agents in the Applicant's laboratories is significant. The hydrazones, hydrazines, semicarbazones and thiosemicarbazones derived from pyridyl ketones of this invention are potent, orally active, nonneurotoxic EAA antagonists that hold promise for commercial development as nontoxic, clinically useful antiepileptic drugs for the management of epilepsy in humans.